The FHIT Gene at 3p14.2 Is Abnormal in Lung Cancer

presence of at least one tumor suppressor gene in this chromosomal region. However, the observation that allelic losses often involve most of 3p has hampered the isolation of the involved gene(s). Candidate loci have been identified such as the von Hippel–Lindau gene, located at 3p25, located in a region within 3p21 were reported to be sites of recurrent homozygous deletions in SCLC (Daly et al., To determine the role of the FHIT gene, which encom-Very recently, we identified the human FHIT gene (for passes the fragile site at 3p14.2, we analyzed 59 tu-fragile histidine triad) using an exon trapping strategy mors of the small cell and non-small cell type by re-from cosmids covering a specific region at 3p14.2 inverse transcription of FHIT mRNA, followed by PCR volved in homozygous deletions in epithelial cancer cell amplification and sequencing of products. losses affecting the gene were evaluated by microsa-member of the histidine triad (HIT) gene family, is a tellite polymorphism analysis and genomic alterations highly conserved gene homologous to a group of genes by hybridization using cDNA and genomic probes. identified in prokaryotic and eukaryotic organisms. The Small cell lung tumors (80%) and non-small cell lung FHIT protein shows 69% similarity to a Schizosaccharo-cancers (40%) showed abnormalities in RNA tran-myces pombe enzyme, diadenosine 5Ј,5ЈЈЈ-P 1 ,P 4-tetra-scripts of FHIT, and 76% of the tumors exhibited loss phosphate (Ap 4 A) asymmetrical hydrolase (Huang et al., of FHIT alleles. Abnormal lung tumor transcripts lack 1995), which cleaves the Ap 4 A substrate asymmetrically two or more exons of the FHIT gene. Small cell lung into ATP and AMP. cancer tumors and cell lines were analyzed by South-The FHIT gene is disrupted by the t(3;8) chromosomal ern blotting and showed rearranged BamHI fragments. translocation observed in a family with renal cell carci-These data suggest a critical role of the FHIT gene in noma and contains the FRA3B fragile site and the target lung carcinogenesis. of homozygous deletions in various human cancer-derived cell lines. Moreover, the study by Ohta et al. (1996) demonstrated that FHIT gene abnormalities often occur Introduction in primary digestive tract cancers. Considering that the highest frequency of allelic dele-Lung cancer is a major cause of mortality worldwide, and tions in lung cancer is on 3p and that tumors linked to the overall survival rate has not improved significantly in carcinogenic exposure could be especially susceptible the last 20 years. The understanding …